ClinVar Genomic variation as it relates to human health
NM_003054.6(SLC18A2):c.710C>A (p.Pro237His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(1); Likely pathogenic(1); Uncertain significance(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003054.6(SLC18A2):c.710C>A (p.Pro237His)
Variation ID: 666409 Accession: VCV000666409.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q25.3 10: 119014797 (GRCh37) [ NCBI UCSC ] 10: 117255286 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 26, 2019 Apr 6, 2024 Mar 26, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003054.6:c.710C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003045.2:p.Pro237His missense NC_000010.11:g.117255286C>A NC_000010.10:g.119014797C>A - Protein change
- P237H
- Other names
- -
- Canonical SPDI
- NC_000010.11:117255285:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
SLC18A2 | - | - |
GRCh38 GRCh37 |
159 | 208 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (1) |
no assertion criteria provided
|
Jun 26, 2015 | RCV000824911.2 | |
Conflicting interpretations of pathogenicity (6) |
criteria provided, conflicting classifications
|
Mar 26, 2024 | RCV001420581.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 12, 2022 | RCV003558600.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Uncertain significance
(Jul 03, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinsonism-dystonia, infantile, 2
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV001622896.1 First in ClinVar: May 21, 2021 Last updated: May 21, 2021 |
Clinical Features:
Intellectual disability (present) , Autism (present) , Delayed speech and language development (present) , Joint hypermobility (present) , Hypotonia (present)
Secondary finding: no
|
|
Pathogenic
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinsonism-dystonia, infantile, 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital
Accession: SCV002765164.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Age: 0-9 years
Sex: male
Ethnicity/Population group: Arab
|
|
Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinsonism-dystonia, infantile, 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100610.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.P237H in SLC18A2 (NM_003054.6) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The … (more)
The missense variant p.P237H in SLC18A2 (NM_003054.6) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant has been submitted to ClinVar as Uncertain signifcance but no details are avialable for an independent assessment. The p.P237H variant is observed in 4/1,13,688 (0.0035%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.P237H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.710 in SLC18A2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. (less)
Clinical Features:
Seizure (present) , Global developmental delay (present) , Cognitive impairment (present) , Abnormality of limbs (present) , Dystonic disorder (present) , Emotional lability (present)
|
|
Uncertain significance
(Aug 19, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinsonism-dystonia, infantile, 2
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003823331.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
Likely pathogenic
(Dec 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV004295730.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to … (more)
Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 666409). This missense change has been observed in individuals with brain dopamine-serotonin vesicular transport disease (PMID: 26497564, 28716265, 34078222). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs767337086, gnomAD 0.004%). This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 237 of the SLC18A2 protein (p.Pro237His). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
|
|
Uncertain significance
(Mar 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Parkinsonism-dystonia, infantile, 2
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004807365.1
First in ClinVar: Apr 06, 2024 Last updated: Apr 06, 2024 |
|
|
Likely pathogenic
(Jun 26, 2015)
|
no assertion criteria provided
Method: research
|
Brain dopamineâ€serotonin vesicular transport disease
(Autosomal recessive inheritance)
Affected status: yes, no
Allele origin:
germline
|
Applied Translational Genetics Group, University of Auckland
Accession: SCV000238543.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
Homozygous recessive inheritance of a variant causing substitution of an evolutionary conserved amino acid; variant present in a heterozygous state in a single ExAC sample … (more)
Homozygous recessive inheritance of a variant causing substitution of an evolutionary conserved amino acid; variant present in a heterozygous state in a single ExAC sample but not reported elsewhere (less)
Observation 1:
Clinical Features:
Muscular hypotonia (present) , Neurodevelopmental delay (present) , Generalized myoclonic seizures (present)
Indication for testing: Infantile muscular hypotonia, Developmental delay
Family history: yes
Age: 10-19 years
Sex: male
Ethnicity/Population group: European
Geographic origin: New Zealand
Tissue: Blood
Segregation observed: yes
Secondary finding: no
Method: Agilent SureSelect V5
Observation 2:
Clinical Features:
Muscular hypotonia (present) , Neurodevelopmental delay (present) , Generalized myoclonic seizures (present)
Indication for testing: Infantile muscular hypotonia, Developmental delay
Family history: yes
Age: 0-9 years
Sex: male
Ethnicity/Population group: European
Geographic origin: New Zealand
Tissue: Blood
Segregation observed: yes
Secondary finding: no
Method: Agilent SureSelect V5
Observation 3:
Clinical Features:
none (present)
Family history: no
Age: 60-69 years
Sex: male
Ethnicity/Population group: European
Geographic origin: New Zealand
Tissue: Blood
Segregation observed: yes
Secondary finding: no
Method: Sanger sequencing
Observation 4:
Clinical Features:
none (present)
Family history: no
Age: 40-49 years
Sex: female
Ethnicity/Population group: European
Geographic origin: New Zealand
Tissue: Blood
Segregation observed: yes
Secondary finding: no
Method: Sanger sequencing
|
|
Pathogenic
(Dec 12, 2023)
|
no assertion criteria provided
Method: literature only
|
PARKINSONISM-DYSTONIA, INFANTILE, 2
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV004175903.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment on evidence:
In 2 sibs, born to consanguineous parents, with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Jacobsen et al. (2016) identified homozygosity for a c.710C-A transversion (c.710C-A, NM_003054.4) in … (more)
In 2 sibs, born to consanguineous parents, with infantile parkinsonism-dystonia-2 (PKDYS2; 618049), Jacobsen et al. (2016) identified homozygosity for a c.710C-A transversion (c.710C-A, NM_003054.4) in the SLC18A2 gene, resulting in a pro237-to-his (P237H) substitution. The mutation, which was identified by SNP homozygosity mapping and whole-exome sequencing, segregated with disease in the family. The mutation was present in the ExAC database at an allele frequency of 8.144 x 10(-6). In a 7-year-old girl, born to consanguineous Iraqui parents, with PKDYS2, Rath et al. (2017) identified homozygosity for the P237H mutation in the SLC18A2 gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents and 7 unaffected sibs. DNA of a deceased, similarly affected sib showed homozygosity for the P237H mutation. In a 6-month-old male with PKDYS2, Zhai et al. (2023) identified homozygosity for the P237H mutation in the SLC18A2 gene. The mutation was identified by trio whole-exome sequencing and SNP array analysis. The patient's father was a mutation carrier, and homozygosity for the P237H mutation arose from paternal uniparental disomy of chromosome 10p15.3q26.3. (less)
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals. | Saida K | Genetics in medicine : official journal of the American College of Medical Genetics | 2023 | PMID: 36318270 |
A case report of infantile parkinsonism-dystonia-2 caused by homozygous mutation in the SLC18A2 gene. | Zhai H | The International journal of neuroscience | 2023 | PMID: 34078222 |
Exome sequencing results in identification and treatment of brain dopamine-serotonin vesicular transport disease. | Rath M | Journal of the neurological sciences | 2017 | PMID: 28716265 |
Brain dopamine-serotonin vesicular transport disease presenting as a severe infantile hypotonic parkinsonian disorder. | Jacobsen JC | Journal of inherited metabolic disease | 2016 | PMID: 26497564 |
Text-mined citations for rs767337086 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.